This new investigator application details a proposal to identify the normal function of A[unreadable], the leading pathological agent in Alzheimer's disease (AD). A[unreadable] is most often characterized as an incidental catabolic byproduct of the amyloid precursor protein (APP) with no functional role. However, a detailed comparison of A[unreadable] and the archetypical human antimicrobial peptide (AMP) LL-37 reveals striking similarities in physiochemical and biological activities. Properties and actions cited as abnormal pathological behavior for A[unreadable] mediate normal functions of LL-37. We propose that the physiochemical and biological activities of A[unreadable] are consistent with a primary function as an antimicrobial peptide of the innate immune system. Consistent with our hypothesis preliminary experiments show A[unreadable] inhibits the growth of eight clinically important microorganisms, including Candida albicans, Escherichia coli, Staphylococcus epidermidis, Streptococcus pneumoniae, Staphylococcus aureus, Listeria monocytogenes, Enterococcus faecalis, and Streptococcus agalactiae. A[unreadable] is a more potent antimicrobial agent than LL-37 for at least two of these microorganisms. Furthermore, experiments identified an antimicrobial activity in AD brain homogenates attenuated by anti-A[unreadable] immunodepletion. Extrapolating from the known physiochemistry of A[unreadable] we have also identified novel metal-mediated oligomerization activities for LL-37. Oligomerization is a key step in AMP action and preliminary experiments suggest A[unreadable] oligomers have potentiated antimicrobial activity. Consistent with a key role for oligomers in A[unreadable]s antimicrobial action our preliminary data suggest incubation of the peptide with bacterial cells also promotes oligomerization. Different bacteria species were found to generate distinct A[unreadable] oligomers, including highly neurotoxic SDS-stable dimers and trimers. The proposed study will use established methods from clinical microbiology and molecular biology to characterize the in vitro antimicrobial activity of A[unreadable]. In addition, experiments will investigate the role of oligomers in A[unreadable]s antimicrobial action and if interaction of the peptide with microbial cells generates species with high neurotoxicity. In the final phase of our proposed study experiments will test if APP knockout mice have reduced resistance to bacterial meningitis. Conversely, transgenic mice over-expressing A[unreadable] in the CNS will be tested for increased resistance to bacterial meningitis. Our project is a fresh approach to a long standing and largely ignored aspect of A[unreadable] biology. We feel this line of enquiry has a high probability of yielding real and novel insights that will facilitate better strategies for ameliorating the pathological actions of A[unreadable]. PUBLIC HEALTH RELEVANCE: The key inference of the proposed study is that the biomolecule most associated with AD pathology (A[unreadable]) normally functions as an antimicrobial agent and is a component of the innate immune system. If validated the identification of A[unreadable] as an antimicrobial agent raises the possibility of preventing amyloidosis from starting by preemptive targeting of pathogens/insults that stimulate the brain's innate immune system. Secondly, it identifies the inflammatory pathways of the innate immune system as targets for modulating A[unreadable] generation.